tbuckley/cabot-search huggingface dataset:
Noncanonical Form of ERAD Regulates Cardiac Hypertrophy
Authors: Erik A. Blackwood, Lauren F. MacDonnell, Donna J. Thuerauf, Alina S. Bilal, Victoria B. Murray, Kenneth C. Bedi, Kenneth B. Margulies, Christopher C. Glembotski
Journal: Circulation (2022)

Background: Cardiac hypertrophy increases demands on protein folding, which causes an accumulation of misfolded proteins in the endoplasmic reticulum (ER). These misfolded proteins can be removed by the adaptive retrotranslocation, polyubiquitylation, and a proteasome-mediated degradation process, ER-associated degradation (ERAD), which, as a biological process and rate, has not been studied in vivo. To investigate a role for ERAD in a pathophysiological model, we examined the function of the functional initiator of ERAD, valosin-containing protein–interacting membrane protein (VIMP), positing that VIMP would be adaptive in pathological cardiac hypertrophy in mice. Methods: We developed a new method involving cardiac myocyte-specific adeno-associated virus serovar 9–mediated expression of the canonical ERAD substrate, TCRα, to measure the rate of ERAD, ie, ERAD flux, in the heart in vivo. Adeno-associated virus serovar 9 was also used to either knock down or overexpress VIMP in the heart. Then mice were subjected to transverse aortic constriction to induce pressure overload–induced cardiac hypertrophy. Results: ERAD flux was slowed in both human heart failure and mice after transverse aortic constriction. Surprisingly, although VIMP adaptively contributes to ERAD in model cell lines, in the heart, VIMP knockdown increased ERAD and ameliorated transverse aortic constriction–induced cardiac hypertrophy. Coordinately, VIMP overexpression exacerbated cardiac hypertrophy, which was dependent on VIMP engaging in ERAD. Mechanistically, we found that the cytosolic protein kinase SGK1 (serum/glucocorticoid regulated kinase 1) is a major driver of pathological cardiac hypertrophy in mice subjected to transverse aortic constriction, and that VIMP knockdown decreased the levels of SGK1, which subsequently decreased cardiac pathology. We went on to show that although it is not an ER protein, and resides outside of the ER, SGK1 is degraded by ERAD in a noncanonical process we call ERAD-Out. Despite never having been in the ER, SGK1 is recognized as an ERAD substrate by the ERAD component DERLIN1, and uniquely in cardiac myocytes, VIMP displaces DERLIN1 from initiating ERAD, which decreased SGK1 degradation and promoted cardiac hypertrophy. Conclusions: ERAD-Out is a new preferentially favored noncanonical form of ERAD that mediates the degradation of SGK1 in cardiac myocytes, and in so doing is therefore an important determinant of how the heart responds to pathological stimuli, such as pressure overload.
Monoclonal Antibodies against Malaria
Authors: Umberto D’Alessandro
Journal: New England Journal of Medicine (2022)

Malaria is both a consequence and a cause of poverty and inequality.1 A malaria-free world, in addition to preventing disease and deaths, would stimulate development and economic growth, improving the lives of hundreds of millions of people. Although the global malaria burden has decreased substantially during the past 20 years, progress has stalled since 2014; in 2020, 29 countries accounted for 96% of malaria cases globally, and 6 African countries accounted for approximately 55% of all cases globally.2 Currently available interventions for malaria control are unlikely to achieve the vision of a malaria-free world. The drive toward the elimination and . . .
In acutely ill inpatients, benefits and harms of anticoagulants for VTE prophylaxis were assessed
Authors: Sudeep Shivakumar
Journal: Annals of Internal Medicine (2022)

Eck RJ, Elling T, Sutton AJ, et al. Anticoagulants for thrombosis prophylaxis in acutely ill patients admitted to hospital: systematic review and network meta-analysis. BMJ. 2022;378:e070022. 35788047.
Genomic Analyses Reveal Association of <i>ASIP</i> with a Recurrently evolving Adaptive Color Pattern in Frogs
Authors: Sandra Goutte, Imtiyaz Hariyani, Kole Deroy Utzinger, Yann Bourgeois, Stéphane Boissinot
Journal: Molecular Biology and Evolution (2022)

Traits shared among distantly related lineages are indicators of common evolutionary constraints, at the ecological, physiological, or molecular level. Here, we show that the vertebral stripe, a cryptic color pattern, has evolved hundreds of times in the evolutionary history of anurans (frogs and toads) and is favored in terrestrial habitats. Using a genome-wide association study, we demonstrate that variation near the Agouti signaling protein gene (ASIP) is responsible for the different vertebral stripe phenotypes in the African grass frog Ptychadena robeensis. RNAseq and real-time quantitative PCR revealed that differential expression of the gene and an adjacent long non-coding RNA is linked to patterning in this species. Surprisingly, and although the stripe phenotypes are shared with closely related species, we found that the P. robeensis alleles are private to the species and unlikely to evolve under long-term balancing selection, thus indicating that the vertebral stripe phenotypes result from parallel evolution within the group. Our findings demonstrate that this cryptic color pattern evolved rapidly and recurrently in terrestrial anurans, and therefore constitutes an ideal system to study repeated evolution.
Safety and Efficacy of a Monoclonal Antibody against Malaria in Mali
Authors: Kassoum Kayentao, Aissata Ongoiba, Anne C Preston, Sara A Healy, Safiatou Doumbo, Didier Doumtabe, Abdrahamane Traore, Hamadi Traore, Adama Djiguiba, Shanping Li, Mary E Peterson, Shinyi Telscher, Azza H Idris, Neville K Kisalu, Kevin Carlton, Leonid Serebryannyy, Sandeep Narpala, Adrian B McDermott, Martin Gaudinski, Siriman Traore, Hamidou Cisse, Mamadou Keita, Jeff Skinner, Zonghui Hu, Amatigué Zéguimé, Adama Ouattara, M'Bouye Doucoure, Amagana Dolo, Abdoulaye Djimdé, Boubacar Traore, Robert A Seder, Peter D Crompton
Journal: New England Journal of Medicine (2022)

CIS43LS is a monoclonal antibody that was shown to protect against controlled Plasmodium falciparum infection in a phase 1 clinical trial. Whether a monoclonal antibody can prevent P. falciparum infection in a region in which the infection is endemic is unknown.We conducted a phase 2 trial to assess the safety and efficacy of a single intravenous infusion of CIS43LS against P. falciparum infection in healthy adults in Mali over a 6-month malaria season. In Part A, safety was assessed at three escalating dose levels. In Part B, participants were randomly assigned (in a 1:1:1 ratio) to receive 10 mg of CIS43LS per kilogram of body weight, 40 mg of CIS43LS per kilogram, or placebo. The primary efficacy end point, assessed in a time-to-event analysis, was the first P. falciparum infection detected on blood-smear examination, which was performed at least every 2 weeks for 24 weeks. At enrollment, all the participants received artemether-lumefantrine to clear possible P. falciparum infection.In Part B, 330 adults underwent randomization; 110 were assigned to each trial group. The risk of moderate headache was 3.3 times as high with 40 mg of CIS43LS per kilogram as with placebo. P. falciparum infections were detected on blood-smear examination in 39 participants (35.5%) who received 10 mg of CIS43LS per kilogram, 20 (18.2%) who received 40 mg of CIS43LS per kilogram, and 86 (78.2%) who received placebo. At 6 months, the efficacy of 40 mg of CIS43LS per kilogram as compared with placebo was 88.2% (adjusted 95% confidence interval [CI], 79.3 to 93.3; P<0.001), and the efficacy of 10 mg of CIS43LS per kilogram as compared with placebo was 75.0% (adjusted 95% CI, 61.0 to 84.0; P<0.001).CIS43LS was protective against P. falciparum infection over a 6-month malaria season in Mali without evident safety concerns. (Funded by the National Institute of Allergy and Infectious Diseases; ClinicalTrials.gov number, NCT04329104.).
Implications of <i>Dobbs</i> for the (Re)Criminalization of Intimacy Among LGBTQ Individuals
Authors: Joanne D. Rosen, Chris Beyrer
Journal: JAMA (2022)

This Viewpoint outlines how the revival of now defunct state-level antisodomy laws would harm the health care of LGBTQ individuals should the US Supreme Court reverse itself and urges medical professionals and their societies to advocate for the immediate abolition of antisodomy laws.
The <i>A</i> Word—Our Collective Scarlet Letter
Authors: Melissa A. Simon
Journal: JAMA Surgery (2022)

Our website uses cookies to enhance your experience. By continuing to use our site, or clicking "Continue," you are agreeing to our Cookie Policy | Continue JAMA Surgery HomeNew OnlineCurrent IssueFor Authors Podcast Publications JAMA JAMA Network Open JAMA Cardiology JAMA Dermatology JAMA Health Forum JAMA Internal Medicine JAMA Neurology JAMA Oncology JAMA Ophthalmology JAMA Otolaryngology–Head & Neck Surgery JAMA Pediatrics JAMA Psychiatry JAMA Surgery Archives of Neurology & Psychiatry (1919-1959) JN Learning / CMESubscribeJobsInstitutions / LibrariansReprints & Permissions Terms of Use | Privacy Policy | Accessibility Statement 2023 American Medical Association. All Rights Reserved Search All JAMA JAMA Network Open JAMA Cardiology JAMA Dermatology JAMA Forum Archive JAMA Health Forum JAMA Internal Medicine JAMA Neurology JAMA Oncology JAMA Ophthalmology JAMA Otolaryngology–Head & Neck Surgery JAMA Pediatrics JAMA Psychiatry JAMA Surgery Archives of Neurology & Psychiatry Input Search Term Sign In Individual Sign In Sign inCreate an Account Access through your institution Sign In Purchase Options: Buy this article Rent this article Subscribe to the JAMA Surgery journal
More Than 2% of Circulating Tumor Plasma Cells Defines Plasma Cell Leukemia–Like Multiple Myeloma
Authors: Tomas Jelinek, Renata Bezdekova, David Zihala, Tereza Sevcikova, Anjana Anilkumar Sithara, Lenka Pospisilova, Sabina Sevcikova, Petra Polackova, Martin Stork, Zdenka Knechtova, Ondrej Venglar, Veronika Kapustova, Tereza Popkova, Ludmila Muronova, Zuzana Chyra, Matous Hrdinka, Michal Simicek, Juan-Jose Garcés, Noemi Puig, Maria-Teresa Cedena, Artur Jurczyszyn, Jorge J. Castillo, Miroslav Penka, Jakub Radocha, Maria Victoria Mateos, Jesús F. San-Miguel, Bruno Paiva, Ludek Pour, Lucie Rihova, Roman Hajek
Journal: Journal of Clinical Oncology (2022)

Primary plasma cell leukemia (PCL) is the most aggressive monoclonal gammopathy. It was formerly characterized by ≥ 20% circulating plasma cells (CTCs) until 2021, when this threshold was decreased to ≥ 5%. We hypothesized that primary PCL is not a separate clinical entity, but rather that it represents ultra-high-risk multiple myeloma (MM) characterized by elevated CTC levels.We assessed the levels of CTCs by multiparameter flow cytometry in 395 patients with newly diagnosed transplant-ineligible MM to establish a cutoff for CTCs that identifies the patients with ultra-high-risk PCL-like MM. We tested the cutoff on 185 transplant-eligible patients with MM and further validated on an independent cohort of 280 transplant-ineligible patients treated in the GEM-CLARIDEX trial. The largest published real-world cohort of patients with primary PCL was used for comparison of survival. Finally, we challenged the current 5% threshold for primary PCL diagnosis.Newly diagnosed transplant-ineligible patients with MM with 2%-20% CTCs had significantly shorter progression-free survival (3.1 v 15.6 months; P < .001) and overall survival (14.6 v 33.6 months; P = .023) than patients with < 2%. The 2% cutoff proved to be applicable also in transplant-eligible patients with MM and was successfully validated on an independent cohort of patients from the GEM-CLARIDEX trial. Most importantly, patients with 2%-20% CTCs had comparable dismal outcomes with primary PCL. Moreover, after revealing a low mean difference between flow cytometric and morphologic evaluation of CTCs, we showed that patients with 2%-5% CTCs have similar outcomes as those with 5%-20% CTCs.Our study uncovers that ≥ 2% CTCs is a biomarker of hidden primary PCL and supports the assessment of CTCs by flow cytometry during the diagnostic workup of MM.
Durable spike-specific T cell responses after different COVID-19 vaccination regimens are not further enhanced by booster vaccination
Authors: Yacine Maringer, Annika Nelde, Sarah M. Schroeder, Juliane Schuhmacher, Sebastian Hörber, Andreas Peter, Julia Karbach, Elke Jäger, Juliane S. Walz
Journal: Science Immunology (2022)

Several COVID-19 vaccines are approved to prevent severe disease outcome after SARS-CoV-2 infection. Whereas induction and functionality of antiviral antibody response are largely studied, the induction of T cells upon vaccination with the different approved COVID-19 vaccines is less studied. Here, we report on T cell immunity 4 weeks and 6 months after different vaccination regimens and 4 weeks after an additional booster vaccination in comparison with SARS-CoV-2 T cell responses in convalescents and prepandemic donors using interferon-gamma ELISpot assays and flow cytometry. Increased T cell responses and cross-recognition of B.1.1.529 Omicron variant-specific mutations were observed ex vivo in mRNA- and heterologous-vaccinated donors compared with vector-vaccinated donors. Nevertheless, potent expandability of T cells targeting the spike protein was observed for all vaccination regimens, with frequency, diversity, and the ability to produce several cytokines of vaccine-induced T cell responses comparable with those in convalescent donors. T cell responses for all vaccinated donors significantly exceeded preexisting cross-reactive T cell responses in prepandemic donors. Booster vaccination led to a significant increase in anti-spike IgG responses, which showed a marked decline 6 months after complete vaccination. In contrast, T cell responses remained stable over time after complete vaccination with no significant effect of booster vaccination on T cell responses and cross-recognition of Omicron BA.1 and BA.2 mutations. This suggested that booster vaccination is of particular relevance for the amelioration of antibody response. Together, our work shows that different vaccination regimens induce broad and long-lasting spike-specific CD4+ and CD8+ T cell immunity to SARS-CoV-2.
Antioxidants in brain tumors: current therapeutic significance and future prospects
Authors: Xuchen Qi, Saurabh Kumar Jha, Niraj Kumar Jha, Saikat Dewanjee, Abhijit Dey, Rahul Deka, Pingal Pritam, Kritika Ramgopal, Weiting Liu, Kaijian Hou
Journal: Molecular Cancer (2022)

Brain cancer is regarded among the deadliest forms of cancer worldwide. The distinct tumor microenvironment and inherent characteristics of brain tumor cells virtually render them resistant to the majority of conventional and advanced therapies. Oxidative stress (OS) is a key disruptor of normal brain homeostasis and is involved in carcinogenesis of different forms of brain cancers. Thus, antioxidants may inhibit tumorigenesis by preventing OS induced by various oncogenic factors. Antioxidants are hypothesized to inhibit cancer initiation by endorsing DNA repair and suppressing cancer progression by creating an energy crisis for preneoplastic cells, resulting in antiproliferative effects. These effects are referred to as chemopreventive effects mediated by an antioxidant mechanism. In addition, antioxidants minimize chemotherapy-induced nonspecific organ toxicity and prolong survival. Antioxidants also support the prooxidant chemistry that demonstrate chemotherapeutic potential, particularly at high or pharmacological doses and trigger OS by promoting free radical production, which is essential for activating cell death pathways. A growing body of evidence also revealed the roles of exogenous antioxidants as adjuvants and their ability to reverse chemoresistance. In this review, we explain the influences of different exogenous and endogenous antioxidants on brain cancers with reference to their chemopreventive and chemotherapeutic roles. The role of antioxidants on metabolic reprogramming and their influence on downstream signaling events induced by tumor suppressor gene mutations are critically discussed. Finally, the review hypothesized that both pro- and antioxidant roles are involved in the anticancer mechanisms of the antioxidant molecules by killing neoplastic cells and inhibiting tumor recurrence followed by conventional cancer treatments. The requirements of pro- and antioxidant effects of exogenous antioxidants in brain tumor treatment under different conditions are critically discussed along with the reasons behind the conflicting outcomes in different reports. Finally, we also mention the influencing factors that regulate the pharmacology of the exogenous antioxidants in brain cancer treatment. In conclusion, to achieve consistent clinical outcomes with antioxidant treatments in brain cancers, rigorous mechanistic studies are required with respect to the types, forms, and stages of brain tumors. The concomitant treatment regimens also need adequate consideration.
TKIs for <i>ROS1</i>+ Cancers Get High Marks
Journal: Cancer Discovery (2022)

Next-generation tyrosine kinase inhibitor candidates are continuing to emerge for patients with tumor types harboring ROS1 fusions. Phase I findings from two trials, TRIDENT-1 and ARROS-1, indicate high response rates with repotrectinib and NVL-520, respectively. The latter may be a potential best-in-class agent, with potent ROS1 selectivity that avoids off-target toxicity.
In asymptomatic adults, a COVID-19 Ag-RDT with combined nasal and throat samples had 82% to 89% positive percent agreement
Authors: Thomas Fekete
Journal: Annals of Internal Medicine (2022)

Goodall BL, LeBlanc JJ, Hatchette TF, et al. Investigating the sensitivity of nasal or throat swabs: combination of both swabs increases the sensitivity of SARS-CoV-2 rapid antigen tests. Microbiol Spectr. 2022;10:e0021722 35762772.
In vitro and in vivo efficacy of tecovirimat against a recently emerged 2022 monkeypox virus isolate
Authors: Bryce M. Warner, Levi Klassen, Angela Sloan, Yvon Deschambault, Geoff Soule, Logan Banadyga, Jingxin Cao, James E. Strong, Darwyn Kobasa, David Safronetz
Journal: Science Translational Medicine (2022)

The recent emergence of the monkeypox virus (MPXV) in non-endemic countries has been designated a Public Health Emergency of International Concern by the World Health Organization. There are currently no approved treatments for MPXV infection in the United States or Canada. The antiviral drug tecovirimat (commonly called TPOXX), previously approved for smallpox treatment, is currently being deployed for treatment of MPXV infections where available based on previously accrued data. We tested the efficacy of TPOXX both in vitro and in vivo against a clade 2 Canadian 2022 isolate of MPXV isolated during the current outbreak. TPOXX prevented MPXV replication in vitro with an effective concentration in the nanomolar range. To evaluate TPOXX efficacy in vivo, we first characterized the CAST/EiJ mouse model with the same 2022 Canadian isolate. Unlike previous descriptions of this model, the Canadian isolate was not lethal in CAST/EiJ mice, although it replicated efficiently in the respiratory tract after intranasal infection. Subsequent experiments demonstrated that daily oral TPOXX treatment markedly reduced viral titers in the tissues 1 and 2 weeks after infection. Our data indicate that TPOXX is highly effective against currently circulating MPXV strains and could be an important contributor to curbing the ongoing outbreak.
Comparative Effectiveness and Safety Between Apixaban, Dabigatran, Edoxaban, and Rivaroxaban Among Patients With Atrial Fibrillation
Authors: Wallis C.Y. Lau, Carmen Olga Torre, Kenneth K.C. Man, Henry Morgan Stewart, Sarah Seager, Mui Van Zandt, Christian Reich, Jing Li, Jack Brewster, Gregory Y.H. Lip, Aroon D. Hingorani, Li Wei, Ian C.K. Wong
Journal: Annals of Internal Medicine (2022)

Current guidelines recommend using direct oral anticoagulants (DOACs) over warfarin in patients with atrial fibrillation (AF), but head-to-head trial data do not exist to guide the choice of DOAC.To do a large-scale comparison between all DOACs (apixaban, dabigatran, edoxaban, and rivaroxaban) in routine clinical practice.Multinational population-based cohort study.Five standardized electronic health care databases, which covered 221 million people in France, Germany, the United Kingdom, and the United States.Patients who were newly diagnosed with AF from 2010 through 2019 and received a new DOAC prescription.Database-specific hazard ratios (HRs) of ischemic stroke or systemic embolism, intracranial hemorrhage (ICH), gastrointestinal bleeding (GIB), and all-cause mortality between DOACs were estimated using a Cox regression model stratified by propensity score and pooled using a random-effects model.A total of 527 226 new DOAC users met the inclusion criteria (apixaban, n = 281 320; dabigatran, n = 61 008; edoxaban, n = 12 722; and rivaroxaban, n = 172 176). Apixaban use was associated with lower risk for GIB than use of dabigatran (HR, 0.81 [95% CI, 0.70 to 0.94]), edoxaban (HR, 0.77 [CI, 0.66 to 0.91]), or rivaroxaban (HR, 0.72 [CI, 0.66 to 0.79]). No substantial differences were observed for other outcomes or DOAC-DOAC comparisons. The results were consistent for patients aged 80 years or older. Consistent associations between lower GIB risk and apixaban versus rivaroxaban were observed among patients receiving the standard dose (HR, 0.72 [CI, 0.64 to 0.82]), those receiving a reduced dose (HR, 0.68 [CI, 0.61 to 0.77]), and those with chronic kidney disease (HR, 0.68 [CI, 0.59 to 0.77]).Residual confounding is possible.Among patients with AF, apixaban use was associated with lower risk for GIB and similar rates of ischemic stroke or systemic embolism, ICH, and all-cause mortality compared with dabigatran, edoxaban, and rivaroxaban. This finding was consistent for patients aged 80 years or older and those with chronic kidney disease, who are often underrepresented in clinical trials.None.
Association of Texas’ 2021 Ban on Abortion in Early Pregnancy With the Number of Facility-Based Abortions in Texas and Surrounding States
Authors: Kari White, Gracia Sierra, Klaira Lerma, Anitra Beasley, Lisa G. Hofler, Kristina Tocce, Vinita Goyal, Tony Ogburn, Joseph E. Potter, Samuel L. Dickman
Journal: JAMA (2022)

Texas' 2021 ban on abortion in early pregnancy may demonstrate how patterns of abortion might change following the US Supreme Court's June 2022 decision overturning Roe v Wade.
In hospitalized adults with fever, fever therapy does not reduce mortality or serious adverse events
Authors: Natalia Ovtcharenko, Simon Oczkowski
Journal: Annals of Internal Medicine (2022)

Holgersson J, Ceric A, Sethi N, et al. Fever therapy in febrile adults: systematic review with meta-analyses and trial sequential analyses. BMJ. 2022;378:e069620. 35820685.